Inflammation of the supporting tissues of teeth is a major cause of dental disease in adults. Although the pathogenesis of the common oral inflammatory disease periodontitis is presently unresolved, both humoral and cell-mediated immunity appear to be involved. During early staages of periodontitis, decreased levels of soft tissue collagen and proteoglycan exist. These changes are generally considered to lead to defective soft tissue attachment to teeth. This loss of matrix macromolecules could be explained by: (1) an increased gingival fibroblast production of proteases to degrade these macromolecules, (2) and inhibition of gingival fibroblast proliferation and/or (3) an inhibition of the synthesis of collagen and/or proteoglycan. There is evidence that the cytokine, interleukin-1 (IL-1) is present in increased amounts in inflammatory gingival fluid. Studies, including those from our laboratory, have shown that IL-1 stimulates normal human gingival fibroblast neurtral protease production in culture. We have also obtained preliminary data which suggests that IL-1 may inhibit gingival fibroblast proliferation. These findings suggest that elevated levels of the immune modulator IL-1 may be one way by which immune reactions could contribute to the chronic inflammatory events associated with periodontitis. The main objective of the proposed study is to further understand how IL-1 could alter the metabolism of gingival fibroblasts and lead to loss of the extracellular matrix macromolecules collagen and proteoglycan. We will use human recombinant IL-1 and primary gingival fibroblast cultures derived from gingival tissue obtained from patients undergoing routine periodontal procedures and utilize well established biochemical procedures that are currently performed on a routine basis in our laboratory. These experiments should yield important information on: (1) The types of neutral proteases produced by IL-1 in cultured gingival fibroblasts and the mechanism, (2) The effect of IL-1 on gingival fibroblast proliferation, and (3) The effects of Il-1 on gingival fibroblast collagen and proteoglycan synthesis. These studies will help further elucidate the molecular basis of periodontitis and shed new light on how cell-mediated immune events are coupled to the biochemcial events associated with the tissue destruction of periodontitis. Consequently, an important therapeutic implication of the present proposal is that blockers of Il-1 stimulation of gingival fibroblast metabolism could be useful clinically as a treatment and/or prophylaxis of periodontitis.
